The blood-brain barrier (BBB) is a specialized structure of capillary in the central nervous system (CNS). The BBB consists of three structures: the cerebral capillary endothelium, the choroid plexus epithelium, and the arachnoid membranes. These structures prevent invasion of external substances or molecules that may affect brain functions from penetrating into brain tissue, but also restrict helpful materials access to brain tissue. CNS diseases are hard to be treated due to that the BBB protects brain parenchyma and completely restricts enhanced-permeability/retention (EPR) effect of therapeutic nanoparticles. The BBB serves as an impenetrable barrier to prohibit the delivery of many effective diagnostic agents or therapeutic medicines, thereby reducing the effects of the treatments for CNS diseases.
In addition, the BBB shows low endocytic activity and absence of fenestrations, thus limits the transcellular transport of molecules. In the physiological role, the BBB excluding hydrophobic and larger molecules (>400 Da) from the CNS should be temporarily turned down, and the BBB should open a local delivery to allow the macromolecular substances diffusing to the brain.
Currently, a number of clinical and preclinical researchers attempt to use chemotherapeutic agents in different ways against brain cancers, the ways including: intravenous injection, interstitial injection/implantation, convection-enhanced delivery (CED), and osmotic blood-brain barrier disruption. As to the interstitial injection/implantation and the CED, they are invasive procedures which rely on surgical operations to perform craniotomy. One major disadvantage of the osmotic blood-brain barrier disruption is that if the BBB was globally disrupted, it may hamper specific drug delivery to brain tumor. The limited use of the intravenous injection is due to the systemic toxicity of the intravenous administered therapeutic agents. It limits the allowable dose to be applied. If the amount of drug exceeds the tolerance dose, it will cause systemic adverse effects to patients. Fortunately, this BBB opening effect has been found that it is temporary and could be reversed, and it has no dangerous effects to the neural cells.
In the other hand, in order to enhance efficiency of the brain drug transportation, one way is using modified lipophilic chemicals or hypertonic solution to infuse through the carotid into the brain. The other way is using focused ultrasound. Comparing to the modified chemicals, the advantage of the focused ultrasound that it is a noninvasive procedure, and it can locally open the BBB and minimize the off-target effect. The BBB opening effect will be reserved within several hours, which is a suitable period for drug release. The focused ultrasound also makes rectified (in intact BBB) or increased EPR (in tumor) effect in the brain, that is possibly to achieve local, temporary and noninvasive chemotherapeutic agent delivery. The focused ultrasound therefore is more competitive and attractive to perform and increase local concentration of therapeutic agents in CNS.
Some researchers use proper ultrasound exposure parameters to successfully induce the intact BBB opening effect, the ultrasound driving at burst-tone in week pressure mode can induce the BBB to open. In additionally, the higher acoustic pressure level had been reported to induce a larger scale of BBB opening, the focused ultrasound exposure at different center frequencies will produce different thresholds to induce BBB opening, and the exposure time and consecutive focused ultrasound exposures have been reported to induce molecular penetration in linearly increasing fashion.
Nowadays, medical practitioners expect that the molecule delivery can be predicted, and a more tailor-made CNS drug delivery plan can be made to make the molecule delivered procedure to be more individualized and personalized (i.e., personalized medicine), but it's still unknown that how to predict the scale of molecular penetration under various molecular sizes with the given focused ultrasound exposure parameters. The ultrasound exposure parameters seem multiple and have no direct link with the delivered molecular concentration. The situation makes the treatment of brain diseases to be difficult, and the results are not predictable and controllable.